Medical applications of Technetium (Tc) date from 1958 when the first Tc generator in convenient transportable forms was developed (Tucker, W. D., M. W. Greene, A. J. Weiss, and A. P. Murrenhoff. 1958. Methods of Preparation of Some Carrier-Free Radioisotopes Involving Sorption on Alumina. USAEC Report BNL-3746, Brookhaven National Laboratory, May 29, 1958). Technetium is produced primarily in the VII oxidation state (pertechnetate) in a column or solution through the decay of Mo.sup.99 (VI) present as molybdate, without breakage of chemical bonds. Subsequent developments led to introduction in the mid-60's of a kit system in which the short-lived isotope of pertechnetate could be made available in sterile physiological saline as required for use on site.
Over 85% of routine human nuclear diagnostic procedures now rely upon .sup.99m Tc because of its excellent radiation characteristics (Jones, A. G. 1995. "Technetium in Nuclear Medicine." Radiochimica Acta 70/71:289-297), including (1) a half-life of 6.03 hr; (2) a 0.1405 MeV gamma ray photon that is almost totally absorbed by single, thallium-doped sodium iodide crystal slabs in cameras used for detection; (3) relatively little non-penetrating radiation (no beta particles and low energy auger electrons); and (4) decay to a long-lived groundstate (.sup.99 Tc) that is a low energy, beta emitter. These properties allow the use of higher doses while absorbed radiation dose is maintained at acceptable levels (Steigman, Joseph, and Wiliam C. Eckelman. 1992. The Chemistry of Technetium in Medicine. NAS-NS-3204, Nuclear Science Series, National Academy Press, Washington, D.C.). Thus, .sup.99m Tc offers properties nearly ideal for diagnostic tests, allowing short imaging times and clear images.
The combination of excellent imaging characteristics with the rich chemistry of Tc, which can assume oxidation states ranging from VII to 0 and coordination numbers from 4 to 9, has led to extensive research to find new compounds that target basic physiological functions, organs (e.g., liver, brain, heart, thyroid) and disease states. Research has focused on linking the radionuclide to delivery molecules of biological interest. Representative of this type of effort is the work of Hom, R. K., D. Chi, and J. A. Katzenellenbogen. 1995. "Stereochemical Issues in the Synthesis of bis-bidentate (NS).sub.2 Amino Thiol Complexes of Oxorhenium(V) and Oxotechnetium(V) whose Structures Mimic those of Steroids," pp. 441-443. In Proceedings 11th International Symposium on Radiopharmaceutical Chemistry, Vancouver, August 1995, to develop an agent for assessing breast cancer therapies in which the chelation chemistry of the element is exploited to develop desired in vivo properties, such as lypophilicity, charge and molecular structure.
The most oxidized state of Tc, the pertechnetate ion [Tc(VII)O.sub.4.sup.-1 ], is the primary product of the nuclear production process. The pertechnetate ion itself is highly useful in imaging, but the range of lower oxidation states available for Tc offers a multitude of opportunities to form other chemical species, and the search for compounds of diagnostic value has focused principally on organic complexes with the lower Tc oxidation states. Thus, the reduction of pertechnetate becomes a critical step in exploitation of the full value of this element for diagnosis, in both (1) research to develop new inorganic or organic forms of Tc, and (2) commercial production of compounds that are proven to be of value.
Currently, to administer reduced forms of Tc for diagnostic purposes, the hospital technician usually purchases two kits. The first kit is a Tc generator which includes Mo.sup.99 on a column that is "milked" for the Tc.sup.99m, usually in the form of sodium pertechnetate. A second kit consists of a reaction vial containing, in lyophilized form and under a nitrogen atmosphere, a reducing agent and a complexing agent. Prior to lyophilization, the pH of the second kit is adjusted by the supplier to 4.0-7.5 with hydrochloric acid and sodium hydroxide. The addition of sodium pertechnetate to the second vial results in a chemical reaction reducing the pertechnetate to lower oxidation states that are stabilized in solution by reaction with the complexing agent before intravenous injection into a patient.
Presently, the inorganic compound tin chloride hydrate (SnCl.sub.2.2 H.sub.2 O) is the chemical reducing agent used commercially. However, the complex chemistry of tin has produced a number of undesirable byproducts, including, e.g., excess Sn (II) ions, chlorocomplexes, polymers, colloidal Sn aggregates, "hydrolyzed" Tc and Tc complexes. In addition, excess Sn(II) and the Sn (IV) formed on reduction of Sn (II) complicate formation of the desired Tc complexes because they may form competing complexes (J. Steigman and W. C. Eckelman. 1992. The Chemistry of Technetium in Medicine. NAS-NS-3204, Nuclear Science Series, National Academy Press, Washington, D.C.) The presence of these byproducts has markedly hampered the development of test kits with reduced Tc compounds targeted for specific human organs and has spurred a 20-year search for other more satisfactory reducing agent(s). Other organic and inorganic reducing agents, such as sodium borohydride, hydrazine, hydroxlamine, ascorbic acid and sodium dithionite, have been the subject of extensive research as possible substitutes for Sn but each has disadvantages (e.g., dithionite decomposes in acid solutions) and result in complex chemical residuals that are generally unacceptable for human injection. Thus, there is a great need for new reductants for pertechnetate that offer less potential for toxic, complicated by-products and more potential for developing new Tc compounds for use in medical imaging.
In an unrelated art of environmental cleanup, investigators have suggested that environmental microrganisms may play a role in reduction of Tc in the geologic subsurface. Specifically, Wildung, R. E., K. M. McFadden, and T. R. Garland. 1979. Technetium Sources and Behavior in the Environment. J. Environ. Qual. 8:156-161 suggested that microbial processes may be involved in direct or indirect reduction of Tc in anaerobic soils and sediments. Further, Henrot, J. 1989a. Bioaccumulation and Chemical Modification of Tc by Soil Bacteria. In The Behavior of Technetium in Terrestrial and Aquatic Environs: A Symposium. R. E. Wildung, G. M. Desmet, D. A. Cataldo, and S. G Weiss, (Eds.). Health Physics 57:239-45; and Pignolet, L., Auvary, F., Fonsny, K.,Capot, F., Moureau, Z. 1989b. Role of Various Mcroorganisms on Tc Behavior in Sediments. Health Physics 57:791-800, developed evidence that mixed cultures of anaerobic bacteria alter the solubility of Tc, initially added as pertechnetate, to solutions and marine sediments. D. R. Lovley. 1993. Dissimilatory metal reduction. Annual Reviews of Microbiology 47:263-290 suggested that pertechnetate reduction offered a potential mechanism for removal of Tc from contaminated environments or waste streams. Presumptive evidence for the direct reduction of Tc in the environment has recently come from studies of Tc reduction by the isolated environmental bacteria Shewanella putrifaciens, Geobacter metallireducens (Lloyd, J. R., and L. E. Macaskie. 1996. "A Novel Phosphorlmager-Based Technique for Monitoring the Microbial Reduction of Technetium." Applied and Environmental Microbiology 62:578-582), Chlostridium sphenoides (Francis, A. J., C. J. Dodge, and G. E. Meinken. 1997. "Transformations of Technetium by Denitrifying and Fermentative Bacteria." In proceedings of 97th General Meeting of the American Society for Microbiology, Q-271, Miami Beach, Fla. May. 4-8, 1997, (and Shewanella alga and putrifacians (S. W. Li, A. E. Plymale, Y. A. Gorby, J. K. Fredrickson, J. P. Mckinley, and R. E. Wildung. 1997. Reduction of Technetium by Dissimilatory Metal-Reducing Shewanella sp. International Biometals Symposium. The University of Calgary, August 10-14, 1997), and Desulfovibrio desulfuricans (J. R. Lloyd, H-f. Nolting, V. A. Sole, K. Bosecker, and L. E. Macaskie.1998. Technetium Reduction and Precipitation by Suffate-Reducing Bacteria. Geomicrobiology Journal 15:45-58).
Although environmental microbial reduction of Tc has been suggested, there remains a critical need in the medical imaging art for a process that results in reduced Tc with less chemical impurities. Furthermore, there is a strong need for innovative synthetic approaches that produce new compounds that can be evaluated for expanding the applications of Tc in medical imaging.